2014/01/07

SIRT1 controls liver regeneration by regulating BA metabolism through FXR and mTOR signaling

Sirtuin 1 (SIRT1) is a class III histone deacetylase that tightly controls lipogenesis, protein synthesis, gluconeogenesis, and bile acid (BA) homeostasis. Hence, SIRT1 is considered as a key regulator of cell metabolism. Previous work highlighted the relevance of SIRT1 during aging, as starvation prolonged lifespan in yeast through up-regulation of this deacetylase. In mammals, over-expression of SIRT1 promotes healthy aging and protects mice from tumor development.

In a joint effort leading by the Metabolomics Unit of CIC bioGUNE in collaboration with the University of Salamanca, Medical University Vienna, Spanish National Cancer Research Center (CNIO), la Paz University Hospital and the University of the Basque Country UPV/EHU the imbalance prompts by a chronic excess of SIRT1 in the liver has been exhaustively investigated. In this work published in Hepatology, patients with Hepatocellular Carcinoma from diverse etiologies express high levels of SIRT1. Up-regulation of SIRT1 correlated with down-regulation of FXR in these human liver cancer samples. FXR is the main regulator of BA metabolism as it is essential to preserve BA homeostasis in the liver. Also, FXR is essential for the regeneration of the liver, a compensatory response against injury. Interestingly, the authors found that mice that over-express SIRT1 have impaired liver regeneration. Moreover, SIRT1 overexpressing mice (SIRT) showed persistent deacetylation of FXR and thus altered BA homeostasis, leading to accumulation of BA in the regenerating liver and consequently increased liver injury. SIRT mice also showed impaired mTOR activation, accordingly with the feedback regulation with SIRT1.

Overall, the work of García-Rodríguez et al. point out that SIRT tightly regulates liver regeneration by controlling cell proliferation and BA metabolism through FXR, mTOR, histone methylation and miRNA34. Hence, SIRT1 can be considered as an oncogenic driver thanks to its ability to control BA metabolism through FXR.

Link to the article:
http://www.ncbi.nlm.nih.gov/pubmed/24338587